Genetic studies using astrocyte‐specific APOE manipulations reveal that isoform‐specific effects significantly impact vascular permeability: APOE4 (the major genetic risk factor for AD) compromises BBB integrity through cyclophilin A (CypA)‐mediated signaling cascades, while simultaneously reducing astrocytic end‐foot coverage of blood vessels [65, 66]. This evidence concerns the gene APOE and Alzheimer disease.